Total synthesis by steroids and novel steroid intermediates



United States Patent 01 ice 3,449,382 Patented June 10, 1969 955,52 Int.Cl. C07c 167/02, 169/08, 61/36 U.S. Cl. 260-397.5 Claims ABSTRACT OF THEDISCLOSURE Total synthesis for l3 3-alkyl-3,l7-oXygenated-A gonatrienesand steroid intermediates therefor.

This application is a continuation-in-part application of copending,commonly assigned US. patent application Ser. No. 413,979, filed Nov.25, 1964, now abandoned. This invention relates to a novel process forthe preparation of 13/3-Y-A -gonatrienes of the tormula wherein Y is analkyl radical of 1 to 18 carbon atoms, R is selected from the groupconsisting of hydrogen and an alkyl radical of 1 to 4 carbon atoms, R isselected from the group consisting of hydrogen and an acyl radical of anorganic carboxylic acid having 1 to carbon atoms and Z is selected fromthe group consisting of =0 and It is an object of the invention toprovide a novel total synthesis for steroids.

It is an additional object of the invention to provide novel steroidintermediates of the cformula ROOC II wherein R is selected from thegroup consisting of hydrogen and lower alkyl radicals and Y is an alkylradical of 1 to 18 carbon atoms and to a novel process for theirpreparation.

It is another object of the invention to provide a novel process for thepreparation of the steroid intermediates of Formula II.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

The novel steroid intermediates of the invention are bicyclic compoundsof the [formula ROOC wherein R is selected from the group consisting ofhydrogen and a lower alkyl radical and Y is an alkyl radical of 1 to 18carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, cetyl,etc.

The process of the invention for the preparation of the 13,8-Y-A-gonatrienes of Formula [1 comprises condensing a lower alkyl ester suchas the methyl or ethyl ester of 4-oxo 5-hexenoic acid with aZ-Y-cyclopentane- 1,3-dione wherein Y has the above definition in thepresence of an alkaline condensation agent, treating the condensationproduct with an acid or a mixed acid-base as defined by Lewis to form aracemic mixture of the corresponding 1,5-dioxo-4 (carboxymethyl)-7a-Y-5,6,7, 7a-tetrahydro-indane which is resolved according to knownmethods such as those described in Belgian Patent No. 629,251,separating the dextrorotatory 1,5-dioxo-4- (carboxymethyl) 7amethyl-5,6,7,7a-tetrahydro-indane,

v reducing the dextrorotatory 1,5-dioxo-4-(carboxymethyl)-7a-Y-5,6,7,7a-tetrahydro-indane with an aqueous or aqueous alcoholicalkali metal borohydride to form l-fihydroxy-5-oxo-4-(oarboxymethyl) 7aY-5,6,7,7a-tetrahydro-indane, esterifying the later with an acylatingagent of an organic carboxylic acid having 1 to 10 carbon atoms,catalytically hydrogenating the resulting ester in the presence ofpalladized charcoal to form lp-acyloxy-S- indane, condensing the latterwith a p-lower alkoxy phenyl magnesium bromide to form the correspondinglfi-acyloxy-4 (carboxymethyl) 5 (p-lower alkoxy phenyl)- 7a-Y-3a,4,7,7atetrahydro-indane, catalytically hydrogenating the latter in thepresence orf palladized charcoal to form the corresponding 1Bacyloxy-4-(carboxymethyl)-5-(p-lower alkoxy phenyl)-7a-Y-3a,4,5,6,7,7a-

hexahydro-indane, cyclizing the latter in the presence of HO O C H 0 C MBr J E Home HOOC Y Y Q R: I

OH R:

wherein R is a lower alkyl radical, Y has the above definition, R is anacyl radical of an organic carboxylic acid having 1 to carbon atoms and\R is an alkyl radical of 1 to 4 carbon atoms.

Another method of preparing the 13fi-Y-A -gonatrienes of Formula Icomprises condensing a lower alkyl ester such as the methyl or ethylester of 4-oxo-5-hexenoic acid with a 2-Y-cyclopentane-1,3-dione whereinY has the above definition in the presence of an alkaline condensationagent, treating the condensation product with an acid or a mixedacid-base as defined by Lewis to form a racemic mixture of thecorresponding 1,5-dioxo-4-(carboxymethyl)-7a-Y-5,6,7,7a-tetrahydro-indane which is resolved accordingto known methods such as those described in Belgian Patent No. 629,251,separating the dextrorotatory 1,5 dioxo 4 (carboxymethyl) 7a-methyl-5,6,7,7a-tetrahydroindane, reducing the dextrorotatory 1,5- dioxo-4-(carboxymet-hyl) -7a-Y-5, 6,7,7a-tetrahydro-ind ane with an aqueous oraqueous alcohol alkali metal borohydride to form1-hydroxy-5-oxo-4-(carboxymethyl)-7a- Y-5,6,7,7a-tetrahydro-indane,esterifying the latter with an acylating agent of an organic carboxylicacid having 1 w 10 carbon atoms, condensing the resulting ester with ap-lower alkoxy phenyl magnesium bromide to form 1-acyloxy-4-(carboxymethyl)-5- (p-lower alkoxy phenyl)-7a-Y-7,7a-dihydroindane, catalytically hydrogenating the latter in thepresence of palladized charcoal to form 1-acyloxy-4-(carboxymethyl)-5-(p-lower alkoxy phenyl)-7a-Y-3a,6,7,7a-tetrahydroindane, reducing the latter with lithium inammonia to form 1-acy1oxy-4-(carboxymethyl)- S-(p-lower alkoxyphenyl)-7a-Y-3a,4,5,6,7,7a-hexahydroindane cyclizing the latter in thepresence of polyphosphoric acid to form 3-loweralkoxy-13fi-Y-17fi-acyloxy- A -gonatriene-6-one, catalyticallyhydrogenating the latter in the presence of palladized charcoal to form3-lower alkoxy l3fi-Y-l7fl-acyloxy A gonatriene and simultaneouslydealkylating and saponifying the latter in the presence of a strongmineral acid to form 13 8-Y-A -gonatriene-3,l7B-diol. The reactionscheme is illustrated in Table II.

TABLE II i H HC----C=O CHFCH-CC Hz-C HI-C 0 O R I 0=C CH:

HO O O HO O C l-MEBI R40 on, Jon,

HO O C H0 0 C Y Y 0R; OR; A 3 I R40 3:0

H000 g L Y Y U033 JOE wherein R, Y, R and R have the above definitions.

The condensation initial step may be effected at elevated temperaturesin the presence of a solvent such as benzene hydrocarbons like benzene,toluene, etc., but is preferably effected in the absence of additionalsolvent at normal temperatures, i.e. not above 40 C. The a1- kalinecondensation agent may serve as the reaction solvent and is preferably atertiary base such as pyridine, methyl pyridine, triethylamine, etc.

The treatment of the initial condensation products may be effected underanhydrous conditions with acids such as p-toluene sulfonic acids but ispreferably effected with aqueous solutions of acids such as hydrochloricacid, hydrobromic acid and sulfuric acids since the yields are higher inthe latter case.

In addition to the-1,5-dioxo-4-(carboxymethyl)-'[a-Y- 5,6,7,7atetrahydro-indanes, the reaction product contains a significant amountof epimeric 4-lactones of4-(2'carboxylethyl)-7,8-dioxo-4-hydroxy-l-Y-bicyclo [3,2,1]-octane ofthe formula and usually about 2 to 3% of the ester of 1,5-dioxo-4-(carboxymethyl)-7a-Y-5,6,7,7a tetrahydro-indane corresponding to theester of the starting 4-oxo-5-hexenoate ester and can be removed duringthe recovery of the desired acid.

Examples of suitable 2-Y-cyclopentane-1,3-dione starting compounds are2-methyl-cyclopentane-1,3-dione, 2- ethyl cyclopentane-l,3-dione,2-propyl-cyclopentane-1,3- dione, 2-isopropyl-cyclopentane-1,3-dione,Z-butyl cyclopentane-l,3-dione, 2-cetyl-cylopentane-1,3-dione, etc.

A preferred embodiment of the process of the invention comprisescondensing methyl-4-oxo-5-hexenoate with Z-methyl-cyclopentane-1,3-dionein the presence of a tertiary base such as pyridine and treating thecondensation product with an aqueous acid such as hydrochloric acid toform 1,5-dioxo-4-(carboxymethyl)-7a-methyl-5,6,7,7atetrahydroindane.

The racemic mixture of l,5-dioxo-4-(carboxymethyl)-7a-Y-5,6,7,7a-tetrahydro-indane and its enantiomorphs can be convertedin their lower alkyl esters.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

Example I.Preparation of1,5-dioxo-4-(carboxymethyl)-7a-methyl-5,6,7,7a-tetrahydro-indane 17.75gm. of methyl 4-oxo-5-hexenoate (H. T. Taylor, J. Chem. Soc., 1958, p.3922-3924), 100 mg. of hydroquinone and 12.6 gm. of2-methyl-cyclopentane-1,3-dione in 25 cc. of pyridine were placed insuspension and agitated at room temperature for a period of 24 hoursunder an atmosphere of nitrogen. The mixture was then evaporated undervacuum in a water bath with a maximum temperature of 40 C., and theresidue was taken up in ether and the solution was filtered. Theethereal solution was then evaporated to dryness and the oily residueobtained was heated with 150 cc. of 5 N hydrochloric acid for 2 hours ona steam bath. The solution was then cooled to about 45 C. and ammoniumsulfate was added thereto until crystallization began. Next, thesolution was iced and vacuum filtered and the residue was washed withwater and dried to obtain a mixture of 1,5-dioxo-4-(carboxymethyl) 7amethyl 5,6,7,7a-tetrahydroindane and epimeric lactones of4-(2-carboxyethyl)7,8-dioxo-4-hydroxy-l-methyl-bicyclo [3,2,1 -octane.

The said mixture was taken up in 70 cc. of a saturated aqueous solutionof sodium bicarbonate and the two epimeric lactones which were insolubletherein were removed by filtration, and may be separated by theirdilferential solubility in chloroform or benzene. The less solubleepimer had a melting point of 202 C. while the more soluble epimer had amelting point of 167 C. The filtrate Was acidified with hydrochloricacid to a pH value of l and then was iced for 1 hour and vacuumfiltered. The residue was washed with water and dried to obtain 13.23gm. of 1,5 dioxo 4-(carboxymethyl) -7a-methyl-5,6,7,7a-tetrahydro-indanewhich after recrystallization from water had a melting point of 200 C.

This product occurred in the form of colorless prisms which were veryslightly soluble in ether, acetone, benzene and chloroform, fairlysoluble in water and dilute aqueous acids and soluble in dilute aqueousalkalis and in alcohols.

Analysis.-C H O molecular weight=222.23. Calculated: C, 64.85%; H,6.35%. Found: C, 64.7%; H, 6.5%.

This compound is not described in the literature.

In order to isolate the methyl ester the hydrochloric acidmother-liquors was first saturated with ammonium sulfate and thenextracted with ethyl acetate.

The solvent was distilled off under vacuum and the residue wascrystallized from ether. 4 grams of a mixture were obtained, which weresubjected to chromatography on 200 gm. of silicagel, whereupon elutionswere made first with pure methylene chloride, and then with methylenechloride containing increasing amounts of acetone. The methylenechloride elution fractions containing from 6 to 10% of acetone werecombined and evaporated to dryness. The residue from several repeatedrecrystallations in ethyl acetate yielded 0.4 gm. of methyl ester of1,5- dioxo 4-(carboxymethyl) 7a-methyl 5,6,7,7a-tetrahydro indane havinga melting point of 145 C.

The product occured in the form of colorless prisms which were slightlysoluble in water and dilute aqueous acids, fairly soluble in ether andsoluble in alcohols, acetone, benzene and chloroform.

AnalysisPC H O =236.26. Calculated: C, 66.08%; H, 6.83%. Found: C,65.9%;H, 6.7%.

Example II.-Preparation of the methyl ester of 1,5-dioxo- 4-carboxymethyl) -7a-methyl-S,6,7,7a-tetrahydro-indane A. Esterificationwith methanol.-A solution of 3 gm. of1,5-dioxo-4-(carboxymethyl)-7a-methyl-5,6,7,7a-tetrahydro-indaneprepared in Example I in 50 cc. of methanol was saturated with gaseoushydrochloric acid and then was refluxed for a period of 2 hours. Themethanol was evaporated under vacuum and the residue obtained wasredissolved in ethyl acetate. The said solution was washed first withwater, then with a solution of sodium bicarbonate and again with water,then with a solution of sodium bicarbonate and again with water, driedand distilled under vacuum. The resulting residue was recrystallizedfrom 15 cc. of ethyl acetate to obtain 2.4 gm. (75% yield) of the methylester ofl,5-dioxo-4-(carboxymethyl)-'Za-methyl-5,6,7,7a-tetrahydroindane whichhad a melting point of 145 C.

B. Esterification with diazomethane.-Under agitation, 7 cc. of amethylene chloride solution containing 30 gm./ liter of diazomethanewere added dropwise to a suspension of 1.11 gm. of1,5-dioxo-4-(carboxymethyl)-7a-methyl-5,6,7,7a-tetrahydroindane in 15cc. of methylene chloride cooled on an ice bath. A few drops of aceticacid were then added to destroy the slight excess of diazomethane andthe solvent was removed under vacuum. The residue was crystallized in 6cc. of ethyl acetate to obtain 1.07 gm. yield) of the methyl ester of1,5-dioxo-4- (carboxymethyl) 7a methyl-5,6,7,7a-tetrahydroindane havinga melting point of C.

EXAMPLE III.Preparation of 3-methoxy- A -estratriene17 8-01 StepA.1,5-dioxo-4- (carboxymethyl) 7a-methyl5,6,7,7a-tetrahydroindane (a)Preparation of D() and L(+) threo-l-pnitrophenyl-Z-N,N-dirnethylaminopropane 1,3-diols. A mixture of 50 gm. of D() threo-1-p-nitrophenyl-2-amino-propane-1,3-diol, (prepared according to the method of Controuliset al., J.A.C.S., vol. 71, p. 2463 50 cc. of 98% formic acid and 50 cc.of 30% formol was heated on a steam bath for about 3 hours, and then thereaction mixture was distilled to dryness under vacuum. The oily residuewas dissolved in 150 cc. of water and after 40 cc. of 22 B. ammoniumhydroxide were added, the mixture was maintained at a temperature ofapproximately 80 C. for about 15 minutes. Then 60 cc. more of ammoniumhydroxide were added at a high temperature. The whole mixture was thenallowed to stand at a low temperature for about 1 hour. The formedcrystals were vacuum filtered, washed with water and dried in thecomplete absence of light to obtain 53.5 gm. of D()threo-1-p-nitrophenyl-2-N,N dimethylaminopropane-1,3-diol. 121.6 gm. ofthe raw product was purified by dissolution in 2 N hydrochloric acid,followed by treatment with animal black and recrystallization byaddition of 1 N sodium hydroxide to obtain 113 gm. of pure product,having a melting point of 101 C. and a specific rotation of [a]- =-26::l (c.=1% in ethanol).

The product was slightly soluble in water and soluble in dilute aqueousacids and alcohols.

Analysis.-C H O N molecular weight=240.25. Calculated: C, 54.99%; H,6.71%; N, 11.66%. Found: C, 55.2%; H, 7.0%; N, 11.5%.

This compound is not described in the literature.

'L(-|-)-threo-1pnitrophenyl 2 N,N-dimethylaminopropane1,3-diol wasprepared by starting from L(+)- threo-1-p-nitrophenyl-2-aminopropane 1,3diol according to the same method. The said product had a melting pointof 101 C. and a specific rotation of [a] =+26i1 (c.=l% in ethanol).

The product was slightly soluble in water and soluble in dilute aqueousacids and alcohols.

Analysis.C H O N molecular weight=240.25. Calculated: C, 54.99%; H,6.71%; N, 11.66%. Found: C, 55.0%; H, 6.7%; N, 11.4%.

This compound is not described in the literature.

(b) Resolution of 1,5dioxo-4-carboxymethyl-7amethyl-5,6,7,7a-tetrahydroindane.Under reflux,22.2 gm. of racemic 1,5-dioxo-4-carboxymethyl-7a-methyl-S,6,7,7a-tetrahydroindane from Example I and 24 gm. of D() threo-l-p nitrophenyl-2-N,N-dimethylaminopropane-1,3-diol were dissolved in 100 cc. ofethyl acetate containing 2% water and 7 cc. of ethanol. Crystallizationwas started and the solution was cooled to room temperature over aperiod of about two hours, and then the solution was allowed to standfor 12 hours at a low temperature The crystals formed were vacuumfiltered, washed several times with ethyl acetate containing 1% of waterand finally dried to obtain 21.84 gm. of the desired salt, having amelting point of about 100 C. and a specific rotation of [a] =-|-78- -1(c.=1% in water).

The product was soluble in water and alcohols and slightly soluble inethyl acetate.

This compound is not described in the literature.

(2) Preparation of dextrorotatory 1,5-dioxo-4-(carboxymethyl) 7a methyl5,6,7,7a tetrahydroindane.- Under an atmosphere of nitrogen, 24 gm. ofdextrorotatory salt of D()threo-l-p-nitrophenyl-2-N,N-dimethylaminopropane-1,3-diol withdextrorotatory 1,5-dioxo-4- (carboxymethyl 7a methyl 5,6,7,7atetrahydroindane were introduced into 100 cc. of ice water and then 50cc.

of N sodium hydroxide were slowly added thereto under agitation. Thereaction mixture was filtered and the filtrate was recovered, washedrepeatedly with ethyl acetate, then acidified with concentratedhydrochloric acid. Ammonium sulfate was added up to the point ofsaturation and the mixture was extracted several times with methylenechloride. The extracts obtained were combined, dried over magnesiumsulfate, treated with animal black and dried under vacuum. The residuewas taken up in 20 cc. of toluene and allowed to crystallize. The formedcrystals were vacuum filtered, washed with cold toluene and dried toobtain 10.5 gm. of dextrorotatory 1,5-dioxo-4-(carboxymethyl) 7a methyl5,6,7,7a tetrahydroindane having a melting point of 129 C. and aspecific rotation of [a] =+225 1 (c.=0.5% in water).

The product was slightly soluble in toluene, fairly soluble in water andsoluble in the alcohols and chloroform.

This compound is not described in the literature.

Step B.Preparation of dextrorotatory lfl-hydroxy- 4/3(carboxymethyl)-5-oxo 7afl methyl 5,6,7,7atetrahydroindane.

Under an atmosphere of nitrogen, 6.75 gm. of dextrorotatory 1,5dioxo-413-(carboxymethyl)-7a;8-methyl- 5,6,7,7a-tetrahydroindane weredissolved in the quantity exactly necessary of an aqueous 2 N sodiumhydroxide and the colution was cooled to 0 C. Within 10 minutes at atemperature of about 0 C., a solution of 0.310 gm. of commercial sodiumborohydride in 1.5 cc. of ice water was introduced therein. The mixturewas agitated for 2 minutes after the introduction was completed, thenacidified with concentrated aqueous hydrochloric acid solution. Themixture was held for 1 hour at 0 C., vacuum filtered, washed with icewater and dried to obtain 6.64 gm. of dextrorotatory1/8-hydroxy-4/3-(carboxymethyl) 5 oxo7afi-methyl-5,6,7,7a-tetrahydroindane having a melting point of 194 C. Aportion of this product was purified by crystallization from a mixtureof ethyl acetate and alcohol, followed by recrystallization from Waterto obtain a product with a melting point of 194 C. and a specificrotation of [a] =+32J:1 (c.=0.5'% in ethanol).

Analysis.C H O molecular weight=224.25. Calculated: C, 64.27%, H, 7.19%.Found: C, 64.1%; H, 7.3%.

This compound is not described in the literature.

Step C (a) Preparation of the lactone of dextrorotatory 1f!- acetoxy 5hydroxy 4a (carboxymethyl) 7aflmethyl 3aa,4;8,7,7a tetrahydroindane.In ahydrogenation vessel, 2.625 gm. of dextrorotatory lfi-hydroxy- 4B(carboxymethyl) 5 oxo 7a,?) methyl 5,6,7,7atetrahydroindane weredissolved in a mixture of 25 cc. of acetone and 6.5 cc. of water. 1.5gm. of palladized talc containing 1.9% of palladium was added to themixture and the apparatus was purged, after which the mixture wasagitated under an atmosphere of hydrogen at room temperature until theabsorption of hydrogen was completed. In this manner, the theoreticquantity of hydrogen was absorbed within 7 hours. The catalyst wasremoved by filtration, and the filtrate was concentrated to dryness. 1.4gm. of anhydrous sodium acetate and 50 cc. of acetic anhydride wereadded to the residue obtained, and the mixture was then brought to andmaintained at reflux for 2 hours. Thereafter, the reaction mixture wasconcentrated to dryness under reduced pressure and a mixture of benzeneand ether was added to the residue. The solution was successively washedfirst with ice water, then with a saturated aqueous solution of sodiumbicarbonate and finally again with ice water. The solution was dried andconcentrated to dryness. The residue was purified by subjecting it tochromatography through a column of silica gel to obtain 0.620 gm. of thelactone of dextrorotatory 1B acetoxy 5 hydroxy 4oz (carboxymethyl) 7aBmethyl 3aa,4,8,7,7a tetrahydroindane having a melting point of 125 C.and a specific rotation of [a] =+60i1 (c.=0.6% in chloroform).

This product is not described in the literature.

(b) Hydrolysis to dextrorotatory l 3-hydroxy-4-(carboxymethyl) 5 oxo 7amethyl 3aa,4fi,5,6,7,7ahexahydroindane-0.850 gm. of lactone ofdextrorotatory lfl acetoxy 5 hydroxy 4B (carboxymethyl)- 7a3-methyl-3aa,4fl,7,7a-tetrahydroindane was dissolved in a mixture of 5cc. of 2 N sodium hydroxide and 1 cc. of ethanol. The solution washeated to reflux under agitation and the reflux was maintained for 30minutes. The reaction mixture was then cooled to C. and a concentratedsolution of hydrochloric acid was added dropwise until a pH value of 1was attained. The solution was saturated with ammonium sulfate and theaqueous phase was extracted with ethyl acetate. The extracts werecombined and the solution obtained was dried and concentrated to drynessunder reduced pressure. The residue was triturated at a high temperaturein a mixture of ethyl ether and isopropyl ether and the mixture wasvacuum filtered and dried to obtain 0.675 gm. of dextrorotatory 1Bhydroxy 4 (carboxymethyl) oxo 7aB methyl-3au,48,5,6,7,7a-hexahydroindane having a melting point of 150 C.

This compound is new.

Step D.-Preparation of 1B-formyloxy-4-(carboxymethyl)-5-oxo-7a;8-methyl-3 aoz,4;3,5,6,7,7a-hexahydroindane For a period of 30minutes, 2.75 gm. of 1 3-hydr0xy-4- (carboxymethyl) 5 oxo 7a,? methyl3aa,4fi,5,6, 7,7a-hexahydroindane in cc. of anhydrous formic acid and0.20 gm. of p-toluene sulfonic acid were heated over a steam bath. Atthe end of this period, the solution was cooled and 50 cc. of a solutioncontaining 20% of sodium formate were added andlfi-formyloxy-4-(carboxymethyl) 5 oxo 7a,B methyl 3au,4;3,5,6,7,7ahexahydroindane precipitated therefrom. The solution was kept in arefrigerator for 1 hour, then vacuum filtered, washed first with sodiumformate, then with ice water and finally dried. The product wasrecrystallized at high and low temperatures from ethyl acetate. Theproduct obtained occurred in the form of colorless, prismatic needleswhich were soluble in most of the organic solvents, in water and indilute alkaline solutions.

This compound is new.

Step E.-Preparation of 1/3-hydroxy-4-(carboxymethyl)- 5 p methoxy phenyl7a/3 methyl 3aa,4,B,7,7atetrahydroindane 2.5 gm. of magnesium wereintroduced into 40 cc. of tetrahydrofuran and after the mixture washeated to 30 C., about 10% of a solution of 18.7 gm. of p-bromoanisol in27 cc. of tetrahydrofuran were added thereto. The mixture was agitated,maintained at +30 to 35 C., and after the rest of thep-bromoanisol-tetrahydrofuran solution was added, the reaction mixturewas heated at 3035 C. for 45 minutes. Next the reaction mixture wasallowed to stand for 2 hours, then held at a tempera ture of 0 C. for 1hour and finally returned to room temperature to obtain a solution of1.011.2 N p-anisol magnesium bromide.

First, 5 cc. of tetrahydrofuran, then a solution of 340 mg. of 1Bformyloxy 4 (carboxymethyl) 5 oxo- 7afi methyl 3aa,4fl,5,6,7,7ahexahydroindane in 4 cc. of tetrahydrofuran were added to 10 cc. of thesaid magnesium solution, cooled to +10 C. and the mixture was agitatedfor 30 minutes and then returned to room temperature. Next, the reactionmixture was poured over a mixture of ice and 1.2 cc. of hydrochloricacid. The reaction mixture was extracted with ethyl acetate and theorganic phase was washed with water and extracted with a saturatedaqueous solution of sodium bicarbonate. The bicarbonate phase wasacidified, saturated with ammonium sulfate and finally extracted with amixture of ethyl acetate and tetrahydrofuran. The organic phase wasdried and evaporated to dryness to obtain 340 mg. of raw product whichwas dissolved in 3.4 cc. of acetic acid. Then 0.7 cc. of a mixture ofacetic acid and boron trifluoride was added and the solution was allowedto stand for 45 minutes at room temperature. Then it was poured over iceand extracted with methylene chloride. The organic phase was Washed withwater and extracted with N sodium hydroxide and the alkaline phase wasacidified and filtered. The precipitate was vacuum filtered and washedwith water, and dissolved in 1.5 cc. of ethanol. 3 cc. of water wereadded to the solution, which was iced and vacuum filtered to obtain mg.of lfi-hydroxy 4 (carboxymethyl) 5 p methoxyphenyl- 7a/3 methyl3aa,4fl,7,7a tetrahydroindane, having a melting point of 173 C. Bydiluting the mother liquors with water, a second yield of 18 mg. ofproduct was ob tained which gave a total yield of 29% This compound isnew. Infra-red spectra- Presence of --OH, of -COOH and ofp-methoxyphenyl. Ultra-violet spectra (in ethanol)- Amax, at 225 mu.e=9,469.

A at 263-264 mu. e=19,700.

Characterization in the form of its methyl ester 200 mg. of5-methoxyphenyl-lft-hydroxy-4-(carboxymethyl)-7afl-methyl-3aa,45,7,7a-tetrahydroindanewere dissolved in 2cc. methylene chloride and at a temperature of 0 C.,4 cc. of a solution containing 2% of diazomethane in methylene chloridewere added thereto. After the mixture was allowed to stand for 15minutes, the excess diazomethane was destroyed by the addition of a fewdrops of acetic acid. The mixture was washed first with water, then withsodium bicarbonate, dried over magnesium sulfate and evaporated todryness. The obtained resi due was redissolved in methylene chloride andthe solution was subjected to chromatography through magnesium silicateand eluted with a mixture of methylene chloride and methanol to obtain220 mg. of the methyl ester of the starting product. The infra-redspectra showed the presence of a hydroxyl, of an ester function and ofan aromatic ring. The NMR spectra confirmed the presence of the doublebond in 9(11) [H11 ethylenic proton at 327 HZ.].

This compound is new.

Step F-Preparation of 5-p-methoxyphenyl-lfl-hydroxy- 4(carboxymethyl)flap-methyl 3aa,4B,5,6,7,7a-hexahydroindane A catalystwas prepared from 1.8 gm. of activated carbon, 0.9 gm. of potassiumacetate, cc. of water and 0.9 cc. of 20% palladium chloride solution.The catalyst was completely hydrogenated. The palladium catalyst wascarefully vacuum filtered, washed first with water, then with ethanoland then the catalyst was introduced into a hydrogenation vessel. 3.6gm. 5-p-methoxyphenyl- 1B-hydroxy-4-(carboxymethyl) 7apmethyl-3aa,4;8,7,7atetrahydroindane in 216 cc. of ethanol were addedthereto. A stream of hydrogen was passed through the solution underagitation until 250 cc. of hydrogen were absorbed. Next, the vessel waspurged with nitrogen and the catalyst was separated, vacuum filtered andrinsed with ethanol. The ethanol solutions were combined and distilledto dryness under vacuum. The residue was taken up in 11 cc. of hotisopropyl ether and by cooling and icing S-p-methoxyphenyl-lB-hydroxy-4-(carboxymethyl)-7afimethyl 3aa,4fi,5,6,7,7ahexahydroindane crystallized therefrom. The crystals were separated,vacuum filtered, washed with iced isopropyl ether and finally dried toobtain 3.14 gm. of the product in hexagonal lamella. For the purpose ofanalysis, the product was recrystallized from acetone and water. Theinfra-red spectra showed the 11 presence of a hydroxyl group, a carboxylgroup and an aromatic ring. Ultra-violet spectra (in ethanol) h 224-225mg. e=11,200. Xmax, 277-278 mu. e=1,700. A 284 mp. e=1,450.

absence of a conjugated double bond. NMR spectrain accord with thestructure hydrogen in the 9a position.

1 ;3 hydroxy-S-p-methoxyphenyl 4 (carboxymethyl)-7afi-methyl-3aa,4/3,5,6,7,7a-hexahydroindane occurred in the form ofcolorless crystals which were soluble in dilute aqueous alkalis,alcohols and acetone, slightly soluble in ether and insoluble in water.

This compound is new.

Step GPreparation of 15-acetoxy-4-(carboxymethyl)-5- p methoxy-phenyl7a5 methyl-3 aa,455,6,7,7a-hexahydroindane 1 gm. of1fl-hydroxy-4-(carboxymethyl)-5-p-methoxyphenyl-7a 3-methyl-3a11,43,5,6,7,7a-hexahydroindane was dissolved in 25 cc. of pyridine and whilecooling the solution to between and 5 C., 1 cc. of acetic anhydride wasadded thereto. Next, the mixture was agitated for minutes, and thenpoured into ice water. After standing for 1 hour, the reaction mixturewas filtered and the precipitate formed was vacuum filtered and washedfirst with aqueous sodium bicarbonate, then with water until the washwaters were neutral, and finally dried to obtain 1.06 gm. of1fl-acetoxy-4-(carboxymethyl)-5-p-methoxyphenyl-7afi-methyl-3a04,45,5,6,7,7a-hexahydroindane.

The pure product was prepared by recrystallization from a mixture ofmethylene chloride and isopropyl ether by concentration. The productcrystallized in the form of tetragonal prisms, having a melting point of1;57159 C.

The infra-red spectra showed absence of hydroxyl group, presence of acarboxyl group, presence of an acetoxy group and presence of an aromaticring. The product obtained was soluble in alcohol and acetone, slightlysoluble in ether and insoluble in aqueous media and was decomposed byaqueous alkalis.

Step HPreparation of 3methoxy-1=7 3-acetoxy- A -estratiene-6-one 1.50 of1B-acetoxy-4-(carboxymethyl-S-p-methoxypheny1-7aB-methyl-3aa,4;3,5,6,7,7a-hexahydroindanewere dissolved in 5 cc. of syrupy phosphoric acid (d.=1.75) under lightheating. Then 6.25 gm. of phosphoric anhydride were added in smallportions under constant vigourous agitation. The temperature wasincreased to 100 C. and the reaction mixture was heated over a period of1 hour. Thereafter, the mixture was cooled and ice was added thereto and3-methoxy-17/3-acetoxy-A estratriene-G-one precipitated. The precipitatewas recovered by filtration, washed first with water, then with aqueoussodium bicarbonate and again with water. The product was then purifiedby recrystalization from hot and cold alcohol to obtain 0.67 gm. of3-methoxy-17B- acetoxy-A -estratriene-6-one in the form of colorless,thin plates, having a melting point of 114 C.

The ketone function was characterized by formation of a dinitrophenylhydrazone which was obtained after dissolution of 0.50 gm. of3-methoxy-17 3-acetoxy-A estratriene-6-one in tetrahydrofuran, by theaddition first of 0.2 cc. of hydrochloric acid and by the dropwiseaddition of 10 cc. of a solution of dinitrophenyl hydrazine in ethanol.After separation and purification according to the usual processes, 0.55gm. of the dinitrophenyl hydrazone having a melting point of 265 C. wererecovered.

Step I.Preparation of 3-methoxy-A -estratriene- 17 3-ol-6-one 0.1000 gm.of 3-methoxy-17,8-acetoxy-A -estratriene-6-one was dissolved in 20 cc.of ethanol and 10 cc.

of a N-ethanol solution of potassium hydroxide were added. Then themixture was agitated for 1 hour at room temperature and after, 20 cc. ofwater were added, the reaction mixture was vigorously agitated, whichresulted in the precipitation of 3-methoxy-A -estratriene-17fi-ol-6-one. The reaction mixture was then extracted three times with10 cc. of isopropyl ether and the ether phases were combined, washedwith water, dried and evaporated to dryness under reduced pressure. The3-methoxy-A -estratriene-17fl-ol-6-one was purified by dissolution in aminimum of warm isopropyl ether. 3-methoxy-A -estratriene-17B-ol-6-onewas separated by means of refrigeration. The product was left in therefrigerator overnight, then filtered, Washed with water and dried undervacuum to obtain the product in the form of colorless crystals with amelting point of 81 C. and then 132-135 C.

This product is identical to that described in US. Patent No. 2,974,151.

Step I.Preparation of 3-methoxy-A -estratriene- 17 3-ol-(3-methyl etherof estradiol) At a temperature of 40 C., 10 gm. of activated carbon weresuspended in water and after a 1% solution of PT C1 in hydrochloric acidwas added, the suspension was freely alkalized by addition of sodiumhydroxide. The precipitate formed was isolated, washed repeatedly withwater and alcohol and then suspended in cc. of ethyl alcohol. 0.50 gm.of 3-methoxy-A -estratriene-175- ol-6-one was dissolved in 25 cc. ofethanol and 10 cc. of the catalyst were added thereto. The atmosphere inthe vessel was purged with nitrogen and then a stream of hydrogen waspassed through the suspension for a period of 2 hours at roomtemperature. Thereafter, the solution was filtered and the catalyst waswashed three times with alcohol. The alcohol extracts were combined andevaporated to dryness to obtain 3-methoxy-A -estratriene- 175-01 whichwhen purified by recrystallization from isopropyl ether-petroleum etherhad a melting point of 12l C. and a specific rotation of [a] =+76:3 (Cu-0.5% in chloroform).

The product is identical to that described by Wilds et al. [1. Am. Soc.,vol. 75 (1953), p. 5366].

Various modifications of the process of the invention may be madewithout departing from the spirit or scope thereof, and it is to beunderstood that the invention is to be limited only as defined in theappended claims.

We claim:

1. A process for the preparation of 13/3-Y-A gonatrienes of the formulawherein Y is an alkyl radical of 1 to 18 carbon atoms, R is selectedfrom the group consisting of hydrogen and an alkyl radical of 1 to 4carbon atoms, R is selected from the group consisting of hydrogen and anacyl radical of an organic carboxylic acid having 1 to 10 carbon atomsand Z is selected from the group consisting of =0 and which comprisescondensing a lower alkyl ester of 4-oxo- S-hexenoic acid with a2-Y-cyclopentane-1,3-dione wherein Y has the above definition in thepresence of an alkaline condensation agent, treating the condensationproduct with a compound selected from the group consisting of an acidand a Lewis-type mixed acid base to form a racemic mixture of1,5-dioxo-4-(carboxymethyl)- 7a-Y-5,6,7,7a-tetrahydro-indane which isresolved into its enantiomorphs, separating the dextrorotatory1,5-dioxo-4- (carboXymethyl)-7a-methyl 5,6,7,7a tetrahydro-indane,reducing the latter with a compound selected from the group consistingof an aqueous alkali metal borohydride and an aqueous alcoholic alkalimetal borohydride to forml-hydroXy--oXo-4-(carboxymethyl)-7a-Y-5,6,7,7atetrahydro-indane,esterifying the latter with an acylating agent of an organic carboxylicacid having 1 to carbon atoms, catalytically hydrogenating the resultingester in the presence of palladized charcoal to form l-acyloxy- 5 oxo 4(carboxymethyl) 7a Y 3a,4,5,6,7,7ahexahydro-indane, condensing thelatter with a p-lower alkoxy phenyl magnesium bromide to form thecorresponding 1-acyloxy-4-(carboxymethyl)-5-(p-lower alkoxyphenyl)-7a-Y-3a,4,7,7a tetrahydro indane, catalytically hydrogenatingthe latter in the presence of palladized charcoal to form thecorresponding 1-acyloxy-4-(carboxymethyl)-5-(p-lower alkoxyphenyl)-7a-Y-3a,4,5,6,7,7a hexahydro-indane, cyclizing the latter in thepresence of polyphosphoric acid to form 3-loweralkoxy-13p-Y-l7fiacyloXy-A -gonatriene-6-one, catalyticallyhydrogenating the latter in the presence of palladized charcoal to form3-lower alkoxy-lZap-Y-17B-acyloxy-A gonatriene and simultaneouslydealkylating and saponifying the latter in the presence of a strongmineral acid to form 13fl-Y-A -gonatriene-3,l7B-diol.

2. The process of claim 1 wherein the alkaline initial condensationagent is a tertiary base selected from the group consisting of pyridine,methyl pyridines and triethylamine.

3. The process of claim 1 wherein the ester of 4-oxo- S-hexenoic acid isthe methyl ester.

4. The process of claim 1 wherein the ester of 4-oxo- S-hexenoic acid isthe ethyl ester.

5. The process of claim 1 wherein the initial condensation is effectedat temperatures up to 40 C. in the absence of an organic solvent.

6. The process of claim 1 wherein the initial condensation is effectedat elevated temperatures in a monocyclic aromatic hydrocarbon solvent.

7. The process of claim 1 wherein the initial condensation product istreated with an aqueous mineral acid selected from the group consistingof hydrochloric acid, hydrobromic acid and sulfuric acid.

8. The process of claim 1 wherein the initial condensation product istreated under anhydrous conditions with p-toluene sulfonic acid.

9. A process for the preparation of 13(3-Y-A gonatrienes of the formulawherein Y is an alkyl radical of 1 to 18 carbon atoms, R is selectedfrom the group consisting of hydrogen and an alkyl radical of 1 to 4carbon atoms, R is selected from the group consisting of hydrogen and anacyl radical of an organic carboxylic acid having 1 to 10 carbon atomsand Z is selected from the group consisting of =0 and which comprisescondensing a lower alkyl ester of 4-oxo- S-hexenoic acid with a2-Y-cyclopentane-1,3-dione wherein Y has the above definition in thepresence of an alalkaline condensation agent, treating the condensationproduct with a compound selected from the group consisting of an 'acidand a Lewis-type mixed acid base to form a racemic mixture of1,5-dioxo-4-(carboxyrnethyl)- 7a-Y- 5,6,7,7a-tetrahydro-indane which isresolved into its enantiomorphs, separating the dextrorotatory1,5-dioXo-4-(carboxymethyl) 7a methyl-5,6,7,7a-tetrahydroindane,reducing the latter with a compound selected from the group consistingof an aqueous metal borohydride and an aqueous alcoholic alkali metalborohydride to form 1-hydroxy-5-oxo-4-(carboxymethyl)-7a-Y-5,6,7,7a-tetrahydro-indane, esterifying the latter with an acylating agent ofan organic canboxylic acid having 1 to 10 carbon atoms, condensing theresulting ester with a plower alkoxy phenyl magnesium bromide to form 1-acyloxy-4-(carboxymethyl)-5-(p-lower alkoxy phenyl)-7a-Y-7,7a-dihydro-indane, catalytically hydrogenating the latter in thepresence of palladized charcoal to form 1-acyloxy-4-(carboxymethyl)-5-(p-lower alkoxy phenyl)-7a-Y-3a,6,7,7a-tetrahydro-indane, reducing the latter with lithium inammonia to form 1-acyloxy-4-(carboxymethyl) 5 (p-lower alkoxyphenyl)-7a-Y-3a,4,5,6,7,7a-hexahydro-indane, cyclizing the latter in thepresence of polyphosphoric acid to form 3-lower alkoxy-l3 8-Y-l7fl-acyloxy-A -gonatriene-6-one, catalytically hydrogenating the latter in thepresence of p-alladized charcoal to form 3-loweralkoxy-1SB-Y-17B-acloxy-A -gonatriene and simultaneously dealkylatingand saponifying the latter in the presence of a strong mineral acid toform 13,8-Y-A -gonatriene-S,17,3-diol 10. The process of claim 9 whereinthe alkaline initial condensation agent is a tertiary base selected fromthe group consisting of pyridine, methyl pyridines and triethylamine.

11. The process of claim 9 wherein the ester of 4-oxo- S-hexenoic acidis the methyl ester.

12. The process of claim 9 wherein the ester of 4-oxo- S-hexenoic acidis the ethyl ester.

13. The process of claim 9 wherein the initial condensation is effectedat temperatures up to 40 C. in the absence of an organic solvent.

14. The process of claim 9 wherein the initial condensation is effectedat elevated temperatures in a monocyclic aromatic hydrocarbon solvent.

15. The process of claim 9 wherein the initial condensation product istreated with an aqueous mineral acid selected from the group consistingof hydrochloric acid, hydrobromic acid and sulfuric acid.

16. The process of claim 9 wherein the initial condensation product istreated under anhydrous conditions with p-toluene sulfonic acid.

No references cited.

ELBERT L. ROBERTS, Primary Examiner.

US. Cl. X.R.

